Candidate: INO-4800
Category: VAX
Type: DNA vaccine targeting the major surface antigen Spike protein of SARS-CoV-2
2021 Status: Mexico Authorization–INOVIO said September 22 that it received authorization from COFEPRIS (Comisión Federal para la Protección contra Riesgos Sanitarios), the national health regulatory agency of Mexico, to conduct a clinical trial there as part of the global Phase III segment of its Phase II/III INNOVATE (INovio INO-4800 Vaccine Trial for Efficacy) trial (NCT04642638) for INO-4800. Virologically confirmed COVID-19 is the primary endpoint for INNOVATE, which INOVIO plans to conduct with partner Advaccine Biopharmaceuticals Suzhou.
Brazil Authorization–INOVIO said August 26 that it received authorization from ANVISA (Agência Nacional de Vigilância Sanitária), Brazil’s national health regulatory agency, to begin the global Phase III segment of its Phase II/III INNOVATE (INovio INO-4800 Vaccine Trial for Efficacy) trial (NCT04642638). The Phase III segment is designed to assess the efficacy of INO-4800 in a two-dose regimen (2.0 mg per dose), administered one month apart, in a two-to-one randomization in men and non-pregnant women 18 years of age and older in several countries across Latin America, Asia, and Africa.
Expanded Partnership with Advaccine–INOVIO said June 8 that it had expanded a previously-announced partnership with Advaccine Biopharmaceuticals Suzhou in order to jointly conduct the global Phase III segment of the ongoing Phase II/III INNOVATE (INovio INO-4800 Vaccine Trial for Efficacy) trial (NCT04642638) starting in the summer. The companies agreed to evaluate the safety and efficacy of INO-4800 in a two-dose regimen (2.0 mg), administered one month apart, in a two-to-one randomization in subjects 18 years and older across several countries, primarily in Latin America and Asia. The primary endpoint of the Phase III segment will be virologically confirmed COVID-19 disease.
INOVIO and Advaccine said they intended to share equally, subject to specified limitations and conditions, the total cost of the planned global Phase III trial, estimated to be approximately $100 million. The expanded partnership is an extension of an existing relationship between the two companies, including an exclusive agreement announced in January 2021 under which Advaccine has the exclusive rights to develop, manufacture and commercialize INO-4800 within Greater China, inclusive of mainland China, Hong Kong, Macao and Taiwan. Under the expanded agreement, Advaccine obtains rights to additional Asian countries outside of Greater China.
The 2.0 mg dose was selected from the Phase II segment, where INO-4800 was shown to be generally well-tolerated and immunogenic in all tested age groups. Researchers from INOVIO and its clinical partners on May 7 posted a preprint in medRxiv reporting initial positive safety, tolerability and immunogenicity data from the approximately 400-participant Phase II portion of the Phase II/III INNOVATE trial.
The geometric mean fold rise (GMFR) of binding and neutralizing antibody levels were statistically significantly greater in the 2.0 mg dose group versus the 1.0 mg dose group, the researchers reported. The T cell immune responses measured by the ELISpot assay were also higher in the 2.0 mg dose group compared to the 1.0 mg dose group, INOVIO added.
The Phase II portion was designed to evaluate safety, tolerability and immunogenicity of INO-4800 in a 2-dose regimen (1.0 mg or 2.0 mg), in a three-to-one randomization to receive either INO-4800 or placebo, to confirm the more appropriate dosing level for each of three age groups (18-50 years, 51-64 years and 65 years and older) for the subsequent Phase III efficacy evaluation.
The Phase III segment of the INNOVATE trial in the U.S. remains on partial clinical hold until INOVIO satisfactorily resolves the FDA’s remaining questions related to the CELLECTRA® 2000 device that will be used to deliver INO-4800 into the cells of the skin. INOVIO said it plans to satisfy the remaining device questions during the Phase II segment and before the start of the Phase III segment of INNOVATE.
2020 Status: INOVIO on December 7 said it dosed its first patient in the Phase II/III INNOVATE (INovio INO-4800 Vaccine Trial for Efficacy) trial (NCT04642638). The randomized, blinded, placebo-controlled safety and efficacy trial is being funded by the U.S. Department of Defense (DoD) Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) in coordination with the Office of the Assistant Secretary of Defense for Health Affairs (OASD (HA)) and the Defense Health Agency (DHA).
The DoD has agreed to fund both segments of the INNOVATE trial, in addition to $71 million previously announced in June toward large-scale manufacture of the company’s proprietary smart device CELLECTRA® 3PSP and the procurement of CELLECTRA® 2000 devices for the trial.
On December 3, INOVIO said that Kaneka Eurogentec, an affiliate of Kaneka Corp. specializing in DNA plasmid manufacturing, agreed to manufacture INO-4800 at GMP plasmid production scales, under a contract of undisclosed value. Kaneka Eurogentec joined existing partners Thermo Fisher Scientific, Richter-Helm BioLogics and Ology Biosciences in INOVIO’s global manufacturing consortium.
INOVIO received clearance from the FDA to proceed with the Phase II segment of the INNOVATE trial in November. The Phase II segment is designed to evaluate safety, tolerability and immunogenicity of INO-4800 in a 2-dose regimen (1.0 mg or 2.0 mg), in a 3:1 randomization to receive either INO-4800 or placebo for each dose. The segment aims to confirm the most appropriate dose(s) for the Phase III efficacy evaluation in each of three age groups with high risks of infection—18-50 years, 51-64 years and 65 years and older—and is expected to enroll about 400 participants at up to 17 U.S. sites, INOVIO said.
INOVIO acknowledged September 28 that the Phase III portion of the Phase II/III trial had been placed by the FDA on a partial clinical hold pending responses by the company to additional questions from the agency about the trial and its CELLECTRA® 2000 delivery device to be used in the trial. The partial clinical hold remains until INOVIO can satisfactorily address the FDA’s remaining questions related to CELLECTRA 2000. “The company plans to resolve the remaining device questions during the conduct of Phase 2 segment and prior to the start of the Phase 3 segment of the trial,” INOVIO stated November 16.
INOVIO said the partial hold—enrollment of new patients is suspended, though existing ones can continue treatment—was not due to any adverse events related to INOVIO’s ongoing expanded Phase 1 trial of INO-4800 (NCT04336410), which is not impacted by the FDA’s notification. The Phase II/III trial will resume upon resolution of the partial clinical hold and the receipt of external funding to conduct the trial, INOVIO added.
In June, INOVIO’s DNA vaccine for COVID-19 was on track for a Phase II/III trial this summer after generating positive interim Phase I results. According to INOVIO, preliminary analyses of its Phase I results showed that 34 out of 36 trial participants completing the study (94%) “demonstrated overall immune responses” six weeks after receiving two doses of INO-4800 in the study. Participants were enrolled into 1.0 mg or 2.0 mg dose cohorts, with each participant receiving two doses of INO-4800 four weeks apart.
Investors responded with a stock selloff that sent the price of INOVIO stock down 15%, apparently disappointed that the company did not specify the percentage of participants who produced neutralising antibodies to SARS-CoV-2. Two analysts downgraded the company’s stock: Naureen Quibria, PhD, of Maxim Group (from buy to hold), and Jonathan Aschoff, PhD, of Roth Capital Partners (from hold to sell).
The Phase I study (NCT04336410) is an open-label trial designed to evaluate the safety, tolerability and immunological profile of INO-4800 administered by intradermal injection followed by electroporation using the company’s CELLECTRA® 2000 device.
The trial initially enrolled 40 healthy adult volunteers 18 to 50 years of age at two U.S. sites with funding from the Coalition for Epidemic Preparedness Innovations (CEPI). One participant in the 1.0 mg dose cohort and two participants in the 2.0 mg dose cohort were excluded in the immune analyses because they tested positive for COVID-19 immune responses at entry into the study, indicating prior infection. Another participant in the 2.0 mg dose cohort ended involvement in the trial “for reasons unrelated to safety or tolerability,” according to INOVIO.
INOVIO also said it expanded its Phase I trial to add older participants in additional cohorts, and was still on track to begin a planned Phase II/III efficacy trial this summer upon regulatory approval.
A week earlier, INOVIO said it received $71 million from the U.S. Department of Defense (DoD) to support large-scale manufacturing of the company’s CELLECTRA® 3PSP smart device and procurement of CELLECTRA® 2000 devices, which are designed to deliver INO-4800 directly into the skin.
The DoD contract, from the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense Enabling Biotechnologies (JPEO-CBRND-EB) through funding provided by the Defense Health Program, is intended to build upon two separate prior $5 million grants from the Bill & Melinda Gates Foundation and CEPI, to accelerate testing of CELLECTRA 3PSP. Initial development of CELLECTRA 3PSP began in 2019 with $8.1 million from the medical arm of the U.S. Defense Threat Reduction Agency’s Medical CBRN Defense Consortium.
On June 4, the International Vaccine Institute (IVI) and Seoul National University Hospital announced a partnership to start a Phase I/II clinical trial of INO-4800. The two-stage trial of INO-4800—the first clinical study of COVID-19 vaccine approved in Korea—is designed to assess the safety, tolerability, and immunogenicity of the candidate vaccine in 40 healthy adults aged 19-50 years, and will further expand to enroll an additional 120 people aged 19-64 years.
The trial is funded by CEPI through INOVIO and is supported by the Korea Center for Disease Control and Prevention/Korea National Institute of Health.
A day earlier, INOVIO filed a lawsuit against VGXI and its parent company GeneOne Life Science in the Court of Common Pleas of Montgomery County, PA, seeking unspecified monetary damages against the contract manufacturing organization. INOVIO accused VGXI and GeneOne of breaching a contract, then terminating the agreement and treating it as expired after refusing to transfer manufacturing methods, using VGXI’s technology, to two other contract manufacturers, Ology Bioservices and Richter-Helm BioLogics.
INOVIO said it began pursuing the transfer after it was told by VGXI that it did not have the capacity to manufacture the Company’s full order of DNA plasmids on the requested timeline, nor would it be able to manufacture plasmids for the commercial sale of INO-4800. INOVIO said in a regulatory filing that it “has a goal of producing one million doses of INO-4800 by the end of 2020, with its existing capacity and contract resources, for further clinical trials or emergency use.”
In May, INOVIO trumpeted the publication of preclinical data in Nature Communications reporting that INO-4800 showed robust neutralizing antibody and T cell immune responses against SARS-CoV-2 in mice and guinea pigs.
INOVIO investigators collaborated on the study with researchers from Advaccine, Fudan University, Public Health England, the University of Texas, and The Wistar Institute. INOVIO said the researchers used three separate neutralization assays testing the vaccine’s ability to generate antibodies which can block virus infection: An assay using live SARS-CoV-2 viruses; an assay using a pseudo-virus assay, where another virus displays the SARS-CoV-2 Spike protein; and a novel high-throughput surrogate neutralization assay measuring the ability of INO-4800-induced antibodies to block SARS-CoV-2 Spike binding to the host ACE2 receptor.
In April, INOVIO said it will support large-scale manufacturing of INO-4800 by expanding its existing partnership with German contract manufacturer Richter-Helm BioLogics. Richter-Helm planned to use manufacturing technology developed by VGXI, INOVIO’s contract manufacturer for early-stage clinical trial supply. The agreement is partly funded by an initial grant of $1.3 million from CEPI, which brought CEPI’s total support for the development of INO-4800 to $17.2 million.
INOVIO has also said it aims to produce 1 million doses of the vaccine by year’s end for further trials and emergency use, pending regulatory guidance and funding.
Inovio has also teamed up with Advaccine and the International Vaccine Institute to advance clinical trials of INO-4800 in China and South Korea, respectively. Inovio is also assessing preclinical efficacy of INO-4800 in several animal challenge models with Public Health England and Australia’s Commonwealth Scientific and Industrial Research Organization (CSIRO).
In March, Inovio joined biologics CDMO Ology Bioservices to announce that Ology was awarded an $11.9 million Department of Defense (DoD) contract to work with Inovio on DNA technology transfer to rapidly manufacture INO-4800 and deliver it to DoD for upcoming clinical trials. Inovio aims to produce an anticipated one million doses of INO-4800 by year end and said it will seek additional external funding and partnerships to scale up manufacturing capacities.
Inovio was among developers of COVID-19 drug and vaccine candidates highlighted March 22 on CBS’ “60 Minutes.”
Ten days earlier, Inovio said it received a $5 million grant from the Bill and Melinda Gates Foundation to accelerate testing and scale-up of CELLECTRA® 3PSP, a hand-held smart device for the intradermal delivery of INO-4800. Inovio is partnering with Beijing Advaccine Biotechnology on a Phase I trial in China in parallel with the company’s clinical development efforts in the U.S. to develop INO-4800 as a coronavirus treatment.
Inovio will develop INO-4800 through Phase I testing in the U.S., and has launched preclinical testing for clinical product manufacturing. INO-4800 development is also supported by a $9-million grant from CEPI.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types:
● ANTIVIRAL
● VAX
● ANTIBODY
● RNA
